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The vascular endothelium has long been recognized as a key modulator of the detrimental effects of cardiovascular risk factors. Through the release of vasoactive substances, including nitric oxide (NO), a healthy endothelium is cardioprotective. In response to perturbations imposed by enhanced oxidative stress, endothelial dysfunction is associated with atherosclerosis and its consequences. Conduit vessel endothelial function is most commonly measured by assessing flow-mediated dilation (FMD) of the brachial artery. More recently, there has been interest in assessing microvascular function by evaluating the stimulus for FMD, namely hyperemic flow (1). These indexes have been shown to be independent predictors of cardiovascular events (2). Hence, they are accepted atherosclerotic surrogates to evaluate the impact of risk factors and their treatment in clinical research studies.

Obesity has emerged over the past 2 decades as a major global healthcare epidemic (3). It has been recognized as a cardiovascular risk factor through the metabolic consequences of visceral abdominal fat. Adipokines, free fatty acids, inflammatory mediators, and hyperinsulinemia contribute to vascular risk and lead to endothelial dysfunction. Insulin is an NO-mediated vasodilator that also releases endothelin 1; thus, it has complex effects on blood vessel function. Insulin-resistance states are associated with endothelial dysfunction particularly in the microvasculature. Both our group and the Framingham group have shown a relationship among obesity metrics, metabolic syndrome, and peripheral microvascular function (4,5). The distribution of fat appears important because waist circumference adds to body mass index as a predictor of impaired hyperemic flow (6). Visceral fat from patients undergoing bariatric surgery has been shown to have up-regulated proinflammatory gene expression and microvascular endothelial dysfunction, and the degree of adipose inflammation is linked to whole-body insulin resistance and endothelial dysfunction (7).

Prevention of the obesity pandemic is clearly a high priority, but what remains troubling is our limited ability to treat obesity. Lifestyle and dietary interventions have been well studied but have not been particularly effective. Sustained weight loss is difficult to achieve. Favorable effects on metabolic parameters including delayed progression to diabetes can be achieved. However, the impact of these interventions on vascular function measurements has been mixed. More importantly, there are very little data to support that these interventions alter prognosis. The National Institutes of Health–sponsored Look AHEAD (Action for Health in Diabetes) study was recently published. In a cohort of 5,145 patients with obesity and diabetes, intense lifestyle intervention was able to achieve weight loss of 8.6% at 1 year and 6.0% at study end. When the intervention was compared with standard care, there was no difference in cardiovascular outcomes despite some favorable effects on other parameters (8). These are very sobering results.

In this issue of the Journal, Bigornia et al. (9) examine the effect of weight loss on vascular function. The study is novel and important for several reasons: 1) it is much larger than previous work in this field; 2) it evaluates microvascular function in addition to traditional FMD; 3) it shows a differential effect based on insulin levels; and 4) it includes a large cohort of patients undergoing gastric bypass bariatric surgery. A total of 208 obese patients (32% with diabetes) underwent lifestyle intervention alone (48%) or a Roux-en-Y gastric bypass (52%) in a nonrandomized fashion. Vascular function was assessed at baseline and 1 year. A weight loss of >10% was achieved in 112 patients (88% of whom had bariatric surgery), and this weight loss was associated with favorable changes in most metabolic parameters compared with those who did not achieve a 10% weight loss. There was a within-group improvement in microvascular function (hyperemic flow) but no change in FMD.

The researchers then stratified the analysis by the median value of the baseline insulin level (12 μIU/ml) and present some interesting observations. In patients with insulin levels below the median value, even a 10% weight loss was not associated with improvement in either conduit vessel or microvascular function despite favorable effects on vascular metabolic risk factors. In those with insulin levels above 12 μIU/ml, baseline microvascular function was attenuated, and there was a higher burden of risk factors including diabetes. In this group, a 5% weight loss was associated with improvements in microvascular function and a 10% weight loss was associated with improved FMD and hyperemic flow.

1. 10% weight loss target: The first message to take away from the study is that a 10% weight-loss target did achieve significant metabolic improvement and normalization of microvascular function. Recent studies using primarily lifestyle and dietary interventions have achieved weight loss of 5% to 7% and have not shown a favorable effect on large vessel function (10). The relative importance of achieving conduit vessel versus microvascular function improvement has not been clearly established. It is key to point out that the majority of patients in the current study achieved 10% weight loss with bariatric surgery. There have been several small reports of gastric bypass improving FMD, including previous reports by the current researchers. However, the current study is the most convincing and the first to evaluate hyperemic flow. Although the favorable clinical effects of bariatric surgery are beginning to emerge, the SOS (Swedish Obese Subjects) study has followed 2,010 patients who underwent bariatric surgery and a contemporaneous control group for more than 15 years. They demonstrated a decrease in all-cause mortality and cardiovascular events (11). Animal studies have helped to elucidate mechanisms and have demonstrated beneficial effects of gastric bypass on measures of inflammation and oxidative stress.

2. Insulin as a biomarker: The second message is more tantalizing and requires further study. The researchers stratified the analysis based on the median insulin values. One rationale for this was that insulin was an independent predictor of benefit in the SOS study (along with age, diabetes, previous vascular disease, blood pressure, and smoking). In that study, the median value was 17 μIU/ml (compared with 4 to 6 μIU/ml in healthy controls). Thus, in the current study, patients in the “low insulin” (<12 μIU/ml) group still had elevated insulin levels. However, their vascular responses were not modulated by even a 10% weight loss and bariatric surgery. Those in the higher insulin group with 10% weight loss had similar reductions in lipid parameters that could affect endothelial function compared with the low insulin group. However, there was a striking reduction in insulin levels in this group. Insulin resistance is associated with endothelial dysfunction and microvascular dysfunction via abnormalities in a number of signaling pathways, attenuation of NO, up-regulation of inflammatory cytokines and free fatty acids, and a state of oxidative stress. Medical targets of hyperinsulinemia continue to be developed and have achieved some success. Metformin first-line therapy in diabetes has been shown to improve vascular function and attenuate cardiovascular risk. One could speculate that the dramatic decline in insulin levels in the high insulin group, achieved mainly with gastric bypass, led to favorable effects on microvascular and conduit vessel function. This assumption would need to be proven but is supported by some animal studies.

Obesity and insulin resistance are associated with vascular dysfunction, particularly in the microvasculature, leading to enhanced cardiovascular risk. The current study provides strong support for the potential beneficial effects of >10% weight loss, which is mainly achieved through bariatric approaches. Lifestyle, dietary, and exercise approaches to weight loss remain the cornerstone of risk reduction, although they have not convincingly led to improvement in vascular health or decreased number of cardiovascular events. The importance of hyperinsulinemia as a biomarker of weight-loss efficacy is suggested by this study and is hypothesis generating for future work. Whether insulin levels would be used to decide about the suitability of a patient for bariatric surgery is unlikely at this point, given the myriad of beneficial effects on quality of life that this procedure has. However, this information may help inform about expected outcomes and plan the next generation of clinical trials to tackle our growing obesity epidemic.

Footnotes

↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.

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